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Vanderlyle-Preface 3..4 Acromegaly PATHOLOGY, DIAGNOSIS AND TREATMENT DDK0848_FM.inddK0848_FM.indd 1 55/11/05/11/05 99:13:41:13:41 AAMM PProcessrocess CCyanyan PProcessrocess MMagentaagenta PProcessrocess YYellowellow PProcessrocess BBlacklack Acromegaly PATHOLOGY, DIAGNOSIS AND TREATMENT Aart Jan van der Lely Erasmus University Medical Center Rotterdam, The Netherlands Albert Beckers Centre Hospitalier Universitaire de Liège University of Liège Liège, Belgium Adrian F. Daly Centre Hospitalier Universitaire de Liège University of Liège Liège, Belgium Steven W. J. Lamberts Erasmus University Medical Center Rotterdam, The Netherlands David R. Clemmons University of North Carolina Chapel Hill, North Carolina, U.S.A. DDK0848_FM.inddK0848_FM.indd 2 55/11/05/11/05 99:13:42:13:42 AAMM PProcessrocess CCyanyan PProcessrocess MMagentaagenta PProcessrocess YYellowellow PProcessrocess BBlacklack Cover illustrations courtesy of A. Beckers, P. Petrossians, and J. Trouillas. Front cover concept by Stealth Moose Designs. Published in 2005 by Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2005 by Taylor & Francis Group, LLC No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10987654321 International Standard Book Number-10: 0-8493-3848-4 (Hardcover) International Standard Book Number-13: 978-0-8493-3848-9 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Catalog record is available from the Library of Congress Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com Taylor & Francis Group is the Academic Division of T&F Informa plc. Preface Recent years have seen important advances in nearly all aspects of the management of acromegaly. Molecular and genetic studies have brought us closer to understanding the events that lead to tumorigenesis in spora- dic and inherited forms of acromegaly. The criteria for determining disease activity in acromegaly have narrowed in a relatively short period of time and provide a clear yardstick against which we can measure ther- apeutic efficacy. Long-term outcome studies have shown the undoubted benefits of growth hormone (GH) and insulin-like growth factor-I (IGF-I) normalization in terms of reducing mortality in acromegaly to that of the general population, thus providing an added impetus for seeking strict disease control. Incremental refinements in neurosurgical techniques con- tinue to improve outcomes, particularly when performed by a dedicated pituitary surgeon. Innovations in radiotherapy, such as radiosurgery, also promise to control acromegaly, potentially with a lower attendant risk of adverse events. In addition to the established medical therapies, i.e., long-acting somatostatin analogs and dopamine agonists, a new GH receptor antagonist, pegvisomant, has been introduced, which promises to provide control of IGF-I in nearly all patients. These treat- ment options, when used either singly or as a part of multimodal ther- apy, could ensure effective control in all but the most resistant cases of acromegaly. iii iv Preface Acromegaly: Pathology, Diagnosis and Treatment has been written to provide a timely and concise overview of the current management of the disease, and is divided into three broad sections, echoing the title. The first section, Pathology, begins with a timeline that details some of the most important events in the history of the management of acrome- galy. This is followed by a description of the normal function of the pitui- tary and GH–IGF-I axis. The first section ends with an overview of the epidemiology, pathophysiology, and pathological complications of acromegaly. The second section, Diagnosis, concentrates on the clinical, radiological, and hormonal criteria for diagnosing acromegaly, with particular emphasis being placed on the use of modern GH/IGF-I cut- off levels. Treatment, the third section, devotes separate chapters to the relative benefits of the five treatment modalities now available: surgery, somatostatin analogs, a GH-receptor antagonist, dopamine agonists, and radiotherapy. Acromegaly: Pathology, Diagnosis and Treatment is intended for both specialists and interested general physicians alike, as a broad awareness of the disease is important if it is to be diagnosed and treated as early as possible. This book may also be helpful to endocrinology fellows in training and students at the early stages of their careers, providing infor- mation on the care of acromegaly. Finally, we would like to acknowledge the following for their gener- osity to us in terms of their time and also for allowing us to reproduce images contained in the book: Dr. Patrick Petrossians of CHU de Lie`ge and Graphmed (Belgium); Dr. Achille Stevenaert of CHU de Lie`ge (Belgium); Mr. Paul Glacken and the Department of Anatomy, Trinity College (Dublin, Ireland); Mr. Vladimir Chichkov (Tampa, Florida, U.S.A.); Dr. K. Kovacs (Toronto, Canada); Dr. J. Trouillas (Lyon, France); Dr. W. de Herder (Rotterdam, The Netherlands); the A¨ gyptisches Museum, Staatliche Museen zu Berlin (Germany); and Cameraphoto Arte (Venice, Italy). Special thanks to Dr. Serena Dura´n for her insightful com- ments on the content and layout of the manuscript. Our gratitude also goes to the team at Dekker/Taylor & Francis for all of their hard work in making this book a reality. In particular, we would like to thank our commissioning editor, Sandra Beberman, for her tenacity and forbearance throughout the process of completing this publication. Aart Jan van der Lely Albert Beckers Adrian F. Daly Steven W. J. Lamberts David R. Clemmons Contents Preface . ..........................................iii SECTION I: Pathology 1. Acromegaly: A Historical Timeline . .............. 3 Introduction . 3 Prehistory to Imperial Rome . 4 The Middle Ages and the Renaissance . 5 Late 18th to Early 20th Century: Recognition and Description of Acromegaly . 7 Late 19th to Mid-20th Century: Pathology and Treatment . 15 Early 20th Century to Present Day: Physiology and Pharmacotherapy . 19 Conclusion . 24 References . 25 2. The Pituitary Gland: Normal GH/IGF-I Secretion . 29 Anatomy and Structure of the Pituitary Gland . 29 The Growth Hormone–Insulin-Like Growth Factor-I Axis . 31 References . 35 v vi Contents 3. Epidemiology,Pathology, and Complications of Acromegaly . ........................... 39 Epidemiology . 39 Mortality . 40 Pathology: Histopathological Characteristics of Tumors in Acromegaly . 41 Causes of Acromegaly . 50 Complications of Acromegaly . 54 References . 62 SECTION II: Diagnosis 4. Clinical, Endocrine and Radiologic Diagnosis of Acromegaly . 73 Introduction . 73 Clinical Diagnosis and Workup . 73 Endocrine Diagnosis . 83 Radiologic Diagnosis . 85 References . 91 SECTION III: Treatment 5. Surgery . ........................................... 99 Introduction . 99 Technical Approaches to Pituitary Surgery . 99 Preoperative Management . 102 Outcomes of Surgical Treatment of Acromegaly . 103 Repeat Surgery . 104 Adverse Events . 105 References . 105 6. Somatostatin Analogs . .......................... 109 Background . 109 Somatostatin Analogs in Acromegaly: Early Studies . 110 Depot Formulations of Somatostatin Analogs . 110 Efficacy of Long-Acting Somatostatin Analogs . 111 Signs and Symptoms . 113 Tumor Shrinkage . 113 Adverse Events . 114 References . 115 7. Growth Hormone Receptor Antagonist . ............. 121 The Development of Pegvisomant . 121 Pegvisomant in the Treatment of Acromegaly . 123 Contents vii Adverse Events . 127 Pegvisomant: Indications for Treatment . 129 References . 129 8. Dopamine Agonists . ............................. 135 Background . 135 Clinical Studies . 135 Adverse Events . 137 References . 138 9. Radiotherapy . ............................. 141 Background . 141 Efficacy of Radiotherapy in Acromegaly . 141 Adverse Events Associated with Radiotherapy in Acromegaly . 144 Summary . 145 References . 145 Index . .................................... ....147 About the Authors . .................... ....151 Section I PATHOLOGY 1 Acromegaly: A Historical Timeline INTRODUCTION Diseases that significantly alter physical appearance have always aroused human curiosity, and perhaps
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